Role of Nuclear Factor I A (NFIA) gene in glioma

描述（由申请人提供）： 项目摘要：该提案重点关注 Nucear Factor I A (NFIA)（一种神经胶质谱系限制性发育调节基因）在神经胶质瘤发病机制中的潜在作用。 NFIA 转录因子对于 CNS 中神经胶质细胞身份和星形胶质细胞分化的规范至关重要。我的初步数据显示 NFIA 在人类星形细胞瘤中高表达，并且较高的 NFIA 表达与改善的生存率相关。 然而，在实验系统中，NFIA 的过度表达增加了软琼脂中 U87 人 GBM 细胞系的集落形成，并加速了小鼠大脑中 U87 颅内肿瘤的生长。相反，敲低 NFIA (shRNAi) 会导致软琼脂中的菌落变小，培养物中的细胞生长减少，并抑制小鼠中原位 U87 肿瘤的生长。这些发现表明 NFIA 在神经胶质瘤生长中发挥作用，但可能具有不同的肿瘤抑制和肿瘤促进作用。因此，我假设 NFIA 在星形细胞瘤生长中发挥作用，这可能取决于肿瘤中表达的 NFIA 剪接变体。因此，我提出以下具体目标： 1) 确定 NFIA 功能获得 (GOF)/功能丧失 (LOF) 和剪接变异对星形细胞瘤增殖和凋亡的影响。 2) 研究NFIA GOF/LOF和剪接变异对星形细胞瘤迁移和侵袭的影响。 3) 确定剪接变体和 NFIA 的 GOF/LOF 操作对体内 GBM 肿瘤的影响。 我在洛杉矶儿童医院 (CHLA) 的萨班研究所 (SRI) 与 Drs. 建立了高度支持的指导关系。 Anat Erdreich-Epstein 和 Yves DeClerck 参与癌症项目，David Warburton 参与发育生物学项目。此外，我与博士建立了密切的合作。加州理工学院的大卫·安德森。这一提议得到了导师、部门和机构的全力支持。 SRI 的全部资源和核心均可用于我的工作。我计划将我职业生涯的重要部分投入到基础和转化研究中，希望将来能将我的发现转化为临床医学。我打算将神经肿瘤学和神经发育生物学的原理结合起来，以一种新颖的协同方法来寻找神经胶质瘤治疗的新方法。我已经为我当前的研究项目提供了一组有希望的初步数据和具体的实验设计，以及优秀的导师和合作者，这将有助于我成为一名独立的医师科学家的职业目标。 公共健康相关性：实现我的目标将解释 NFIA 表达与患者更好的结果看似不同的关联，但在我的实验系统中加速了肿瘤生长，因此将有助于揭示其在人类神经胶质瘤中的作用及其背后的分子机制。这些知识将支持未来旨在开发恶性神经胶质瘤治疗方法的工作。

DESCRIPTION (provided by applicant): Project Summary: This proposal focuses on the potential role of Nucear Factor I A (NFIA), a glial lineage-restricted developmental regulatory gene, in glioma pathogenesis. NFIA transcription factor is essential for specification of glial identity and astrocyte differentiation in the CNS. My preliminary data show that NFIA is expressed highly in human astrocytomas and higher NFIA expression is associated with improved survival. In experimental systems, however, over-expression of NFIA increased colony formation of U87 human GBM cell line in soft agar and accelerated growth of U87 intracranial tumors in mouse brains. Conversely, knockdown of NFIA (shRNAi) led to smaller colonies in soft agar, reduced cell growth in culture, and inhibited growth of orthotopic U87 tumors in mice. These findings suggest that NFIA has a role in glioma growth but may have differential, tumor-suppressive and tumor-promoting effects. I therefore hypothesize that NFIA has a role in astrocytoma growth, which may depend on the NFIA splice variants expressed in the tumors. I therefore propose the following Specific Aims: 1) To determine the effect of NFIA gain-of-function (GOF)/loss-of-function (LOF) and splice variants in astrocytoma proliferation and apoptosis. 2) To examine the effect of NFIA GOF/LOF and splice variants on astrocytoma migration and invasion. 3) To determine the effect of splice variants and GOF/LOF manipulation of NFIA on GBM tumors in vivo. I have established highly supportive mentoring relationships at The Saban Research Institute (SRI) at Children's Hospital Los Angeles (CHLA) with Drs. Anat Erdreich-Epstein and Yves DeClerck in the Cancer program and David Warburton in Developmental Biology program. In addition I have formed close collaboration with Drs. David Anderson at Caltech. This proposal is fully supported by mentors, department, and institution. The full resources and cores of the SRI are available for my work. I plan to devote a significant part of my career to basic and translational research with the hope to have my findings translated into clinical medicine in the future I intend to combine the principles of Neurooncology and Neurodevelopmental Biology in a novel synergistic approach towards finding new approaches to glioma therapy. I already have a promising set of preliminary data and concrete experimental design for my current research project, as well as outstanding mentors and collaborators, which will facilitate my career goal to become an independent physician-scientist. Public Health Relevance: Achieving my Aims will explain the seemingly divergent association of NFIA expression with better outcome in patients, but accelerated tumor growth in my experimental system, and will thus help uncover its role in human gliomas and the molecular mechanism underlying it. This knowledge will support future work aimed at development of treatments against malignant gliomas.